DESCRIPTION: (Applicant's Description): The etiology of breast cancer is complex and is thought to involve genetic and environmental factors. The strongest known risk factors for breast cancer are inherited mutations of the major susceptibility genes, BRCA1 and BRCA2, but the population attributable risk is low as these mutations are not common. Recent studies suggest that women with mammographic breast density greater than 50% have a three- to five-fold increased risk of breast cancer (Byrne, 1995). Population-based estimates of the prevalence of breast density greater than 50% are 27.7%-32.5% (Boyd, 1995a; Byrne, 1995). Assuming that breast density is causally associated with breast cancer, 28% of breast cancers may be attributable to measures of breast density greater than 50% (Byrne, 1995). With the Minnesota Breast Cancer Resource, we have demonstrated a genetic component to breast density through a segregation analysis that included an adjustment for the influence of epidemiologic risk factors on breast density. We now propose to map this gene(s) by linkage analysis, as the first step in identifying the gene(s) that are responsible for the variability in breast density in these families. The first aim is to obtain DNA from family members who will be used for linkage analysis. We have determined that linkage analysis with approximately 1,000 men and women in 57 families, many of whom we already have blood samples on, will provide sufficient information to map the responsible gene. The second aim is to carry out a genome screen to map the chromosomal location of the gene responsible for the differences in breast density in the families, using linkage analysis. The large sample size should also aid in the detection of genetic heterogeneity, as there may be more than one major gene involved in the genetic regulation of breast density. The third aim is to fine map the genetic region(s) identified through linkage analysis, to identify the smallest genomic segment that contains the gene(s). Studies can then be initiated to identify this gene which may play an important role in breast cancer susceptibility.